Dissolution test equipment

ABSTRACT

Apparatus and method for dissolution testing of active substances in various dosage forms is provided. The apparatus has filtration cells equipped and configured to simulate bodily functions, operate continuously and facilitate testing various types of dosage forms including, but not limited to, tablets, capsules and those having non-disintegrating substrates.

This application claims the benefit of priority under 35 U.S.C. §119(e)of U.S. Provisional Patent Application No. 61/400,889 filed on Aug. 4,2010.

FIELD OF THE INVENTION

The present invention relates to an apparatus and method for testing thedissolution rate of active substances in various dosage forms. Theapparatus includes filtration cells which are designed to simulatebodily functions, operate continuously and facilitate testing varioustypes of dosage forms including, but not limited to, tablets, capsulesand those having non-disintegrating substrates.

BACKGROUND

The rate at which pharmaceutically active compounds dissolve ingastrointestinal fluids is of crucial importance in the design and useof orally administered medications. The active compound must bedissolved before it can be absorbed by the body. The rate at which theactive substance enters into solution is know in the art as thedissolution rate, and the determination of the dissolution rate in vitrois known as dissolution testing.

The concept of using in vitro data to predict or model in vivo behavior,referred to as in vitro—in vivo correlation, or IVIVC, is of greatinterest to the pharmaceutical arts. Test methods with good IVIVC aremuch more capable of detecting problems with existing formulations andin the development of new formulations. Systems which correlate closelywith the dissolution and absorption data obtained in vivo can be used indeveloping dosage forms as well as in the production, scale-up,determination of lot-to-lot variability, testing of new dosagestrengths, testing of minor formulation changes, testing after changesin the site of manufacture and for determining bio-equivalence.

Various methods and devices for dissolution measurement are well knownand described in the art.

The US Food and Drug Administration (US FDA) has issued guidelines onthe levels of correlation that are more or less desirable in in vitrotesting (Guidance for Industry, Extended Release Oral Dosage Forms:Application of In vitro/In vivo Correlations, September 1997). A Level Acorrelation is one that predicts the entire in vivo time course from thein vitro data. A Level B correlation is one that uses statistical momentanalysis. The mean dissolution time is compared either to the meanresidence time or to the mean in vivo dissolution time. A Level Ccorrelation establishes a single point relationship between adissolution parameter and a pharmacokinetic parameter. Level B and LevelC correlations do not reflect the complete shape of the plasmaconcentration-time curve. A Multiple Level C correlation relates invitro data at several time points to several pharmacokinetic parameters.It is generally considered that if a multiple level C is possible, thenLevel A correlation should also be possible. Rank order correlations arethose where only a qualitative relationship exists between in vitro andin vivo. A Level A correlation is considered to be the most informativeand is recommended by the USFDA wherever possible. Multiple Level Ccorrelations can be as useful as Level A, but a Level A is preferred.Having a high level of correlation, eg Level A, can reduce the amount ofin vivo testing necessary for new formulations and can therefore be veryvaluable to pharmaceutical companies.

The conditions that affect dissolution in the gastro-intestinal systemare known to vary with position within the gastro-intestinal system.These variations can affect the rate of dissolution of activesubstances. There have been attempts to simulate these changes in invitro testing. The main focus has been on the very large pH changebetween the stomach and upper GI. This change is large enough to have avery serious effect on the solubility of some active substances. Forexample, diclofenac sodium is essentially insoluble at the low pH of thestomach, but is soluble at the near neutral conditions of the upper GI.In the current art this change of pH has been addressed in two ways. Thefirst has been to change the fluid used in the dissolution test, forexample start with gastric fluid and then change to intestinal fluid.The second has been to change the pH gradually by addition of a higherpH solution. Neither of these methods adequately simulates the pH changein vivo because in both methods all the formulation experiences the pHchange at the same time, whereas in vivo the pH change is controlled bygastric emptying which causes a gradual transfer of the disintegratedformulation so that different portions of the formulation experience thepH changes at different times. In U.S. Pat. No. 5,807,115, Hu statesthat it is difficult to move an already disintegrated solid sample. Huuses this conclusion to justify the gradual change of pH describedabove.

A method that has been used to solve the problem associated with the USPfixed volume and flow-through methods has been the continuous flow cellin which either the contents of the cell is stirred, or a part of theeffluent is recycled to the cell. This allows equilibrium effects to beevaluated.

The equipment described by Huynh-Ngoc and Sirois (J. Pharm Belg, 1976,31, 589-598; ibid 1977, 32, 67-75) is a continuous flow apparatus. Theequipment was designed to facilitate replacement of gastric fluid withintestinal fluid to simulate the transit of the test material throughthe gastrointestinal system. The authors establish only a rank orderIVIVC. Takenaka, Kawashima and Lin (J. Pharm Sci, 69, 1388-1392, 1980)describe an apparatus similar in form to that of Huynh-Ngoc and Sirois.The authors made no connection between their data and in vivoperformance, although it is clear to one skilled in the art that thelimitations will be the same as those for the Huynh-Ngoc and Siroisequipment. Pernarowski, Woo, and Searl (J. Pharm Sci, 57, 1419-1421,1968) also report the use of a continuous flow method. The authors domake comparison of their results with in vivo performance but it is onlya rank order correlation. In all of the flow-through systems describedabove only one cell is used per test. There are multiple cell systemsavailable commercially, but these have multiple cells in parallel sothat each cell is independent of the other and hence they are aplurality of single cell systems. Dissolution testing provides a betterunderstanding of the amount of a pharmaceutically active compoundavailable at a particular absorption site at various times. In addition,establishing a relationship between dosage form and availability of apharmaceutically active compound at certain absorption sites andsystemic blood levels of such active compound aids in the development ofspecialized delivery techniques.

In U.S. Patent Application Publication Nos. 2007/0092404 and2007/0160497, improved continuous flow dissolution test apparati,similar to that described in U.S. Pat. No. 6,799,123 are disclosed,along with methods for using them. In particular, U.S. PatentApplication Publication No. 2007/0092404 describes using a filtersupport in the chamber of the second cell, positioned between the filterand the base (interior bottom surface) of the chamber to preventdistortion of the filter as it collects undissolved solids thereon.

On the other hand, U.S. Patent Application Publication No. 2007/0160497discloses a sample holder device which operates with the sample additionport of the lid of a cell to enable addition and removal of a dosageform to the chamber within the same cell, during continuous operation ofthe multiple flow-through cell dissolution test system, without havingto stop the flow of media or expose the contents of the chamber to theambient environment.

There is also need for an in vitro test that can be used with differentdosage forms of the same active ingredient that gives Level A IVIVC forother dosage forms without the need for different test conditions foreach dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete understanding of the present invention will be gainedfrom the embodiments discussed hereinafter and with reference to theaccompanying drawings, wherein:

FIG. 1 is a schematic representation of one embodiment of the inventioncomprising three cells;

FIG. 2 is a schematic elevational side view of a filtration cell havingan agitator and a shelf screen; and

FIG. 3 is a schematic top plan view of the filtration cell of FIG. 2.

STATEMENT OF THE INVENTION

The present invention relates to an apparatus for conducting dissolutiontests comprising:

a) a first chamber comprising a base and a shelf screen and beingcapable of transferring solid particles to said second chamber;

b) a second chamber connected in series to said first chamber and beingcapable of retaining solids;

c) at least one supply of media that can be continuously passed into oneor more of said chambers;

d) a means of analyzing effluent from said chambers for substances ofinterest in the tests;

e) a means of controlling temperature of medium in each of saidchambers;

wherein each of said chambers has a means of adding a sample and meansfor mixing the sample and medium; and wherein said mixing means of saidfirst chamber is proximate to said base and said shelf screen is held bya retainer and positioned above said mixing means, on an opposite sideof said mixing means from said base.

The sample may be a dosage form comprising one or more activeingredients, one or more inactive ingredients and one or more substratematerial. Furthermore, the dosage form may be a non-disintegratingdosage form wherein at least a portion of said substrate does notdissolve in said medium.

The shelf screen should be a mesh screen compatible with said medium andhaving a have a mesh size of from 200 mesh to 10 mesh.

In one embodiment, the apparatus further comprises a third chamberconnected in series to said second chamber. In such an embodiment, theapparatus may further comprise: at least one supply of media that can becontinuously passed into the third chamber; means for mixing media inthe third chamber; a means of analyzing effluent from the third chamberfor substances of interest.

The present invention also provides a dissolution test method using theabove-described apparatus, comprising the steps of:

a) passing one or more media through at least the first and secondchambers;

b) adding the test sample to the first chamber;

c) passing medium through each of the chambers such that any undissolvedportion of the sample is transferred from the first chamber into thesecond chamber;

d) passing medium through the chambers such that any undissolved portionof the sample remains in the second chamber;

e) maintaining the temperature of the media in the chambers at thedesired temperature for the duration of the test; and

f) analyzing effluent from each of the chambers to determine theconcentration of substance dissolved from the test sample.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an apparatus for conducting dissolutiontests wherein the sample (or dosage form) need not be completelydisintegrated or dissolved in the filtration cell for the test toproceed continuously and accurately. The apparatus comprises a) at leasta first chamber (filtration cell) comprising a base and a shelf screenand being capable of transferring solid particles to said secondchamber; b) a second chamber (filtration cell) connected in series tosaid first chamber and being capable of retaining solids; c) at leastone supply of media that can be continuously passed into one or more ofsaid chambers; d) a means of analyzing effluent from said chambers forsubstances of interest in the tests; and e) a means of controllingtemperature of medium in each of said chambers. Each of thechambers/filtration cells has a means of adding a sample and means formixing the sample and medium (i.e., an agitator). Furthermore, inaccordance with the present invention, and as described in furtherdetail hereinafter, the mixing means of the first chamber is proximateto its base and the shelf screen is held by a retainer and positionedabove the mixing means, on the opposite side of the mixing means fromthe base.

The following terms have the following meanings herein:

The terms “medium”, “media”, or “release medium” as used herein, meansthe liquid medium into which the active substance is being released.Examples of release media can be water, simulated intestinal fluid,simulated gastric fluid, simulated saliva, or the authenticphysiological versions of these fluids, water, and various buffersolutions.

The term “residence time” as used herein, is a well known engineeringconcept applied to continuous flow systems, and is calculated bymathematically dividing the volume of liquid in a vessel by the flowrate into an out of the vessel such that the volume of liquid remainsconstant. For example, a flow rate of 5 ml/min into and out of a vesselcontaining 10 ml of liquid has a residence time of 2 minutes.

The term “dosage form,” “sample,” “composition,” “agent,” “compound”, or“substance” as used herein, means a chemical, a material, a composition,a blend, or a mixture of materials or components that will at leastpartially dissolve within a release medium to release an active agent.The terms characteristics, parameters, and specifications may be usedinterchangeably herein and are intended to refer to some property,ingredient, quantity, quality, etc. of a composition or dosage form.

The term “C_(max)” as used herein, means the maximum concentrationobserved in the blood plasma concentration vs time curve for in vivodata, or the cell effluent concentration vs time curve for in vitrodata.

The term “t_(max)” as used herein, means the time taken to reach C_(max)after the administration of the drug, either in vivo, or in vitro.

The term “gastric chamber” as used herein, refers to the first of threechambers or cells of the current invention, the design and function ofwhich is described hereinbelow.

The term “intestinal chamber” as used herein, refers to the second ofthree chambers or cells of the current invention, the design andfunction of which is described hereinbelow.

The term “circulatory chamber” as used herein, refers to the third ofthree chambers or cells of the current invention, the design andfunction of which is described hereinbelow.

The terms “release profile” and “dissolution profile” as used herein,mean the change in concentration with time of the substance beingtested.

FIG. 1 schematically illustrates one embodiment of the dissolutionapparatus of the present invention. A reservoir (21), a pump (1), and afiltration cell (2) are connected such that the liquid contents of thereservoir (21) are transferred into the filtration cell (2) via the pump(1). The filtration cell (2) is equipped with a tight fitting lid (24),an inlet (28), a shelf screen (3), an agitator (4), an outlet (27)positioned to allow removal of filtered liquid, and a content removalassembly (7). The outlet (27) is connected to a flow-thru uv cell (5)and a pump (6), such that the filtrate is pumped through the uv cell (5)and returned to the inlet of the filtration cell (2). The filtrationcell (2) may also have a sample addition port (8) for providing a dosageform containing one or more active ingredients to the filtration cell(2).

With reference to FIGS. 2 and 3, in accordance with the presentinvention, the agitator (4) is held in the cell (2) by an agitatorsupport (37) and includes a rotating portion (4 a) positioned proximatethe base (36) of the cell (2). The rotating portion (4 a) rotates in aplane parallel to the base (36). The agitator (4) mixes the contents ofthe cell (2), thereby facilitating disintegration and dissolution of thevarious components (i.e., active ingredients, substrate material,inactive ingredients, etc.) of the sample (not shown).

It has been found that as the components of the sample disintegrate anddissolve, larger solid particles sometimes form and drift to the base(36) of the cell (2). Since the distance between the rotating portion (4a) of the agitator (4) and the base (36) or surface of the inner wall(35) of the cell (2) is small, such large solid particles wouldsometimes be large enough to interfere with movement and operation ofthe agitator (4). This, in turn, hindered proper mixing of the cellcontents and required the dissolution test process to be interrupted,and even halted and started all over again with a new sample and freshfluids. Of course, such situations are wasteful of resources and time.In similar fashion, addition of tablets or capsules to the cell (2)without the use of a retaining basket or coil often result in saidtablet or capsule interfering with and stopping the agitator.

To address the foregoing disruptions caused by whole dosage units andsolid particles from the sample (not shown) hindering operation of theagitator (4), a shelf screen (3) which is sized and shaped to fill theentire cross-section of the filtration cell (2) is used as can be seenin FIG. 3. The shelf screen (3) is suspended in the filtration cell (2),above the rotating portion (4 a) of the agitator (4), to catch andretain solids that may form during disintegration and dissolution of thesample. In the embodiment shown in FIGS. 2 and 3, the circumferentialedge of the shelf screen (3) is tightly fitted in a groove (not shownper se) formed on the interior surface of the wall (35) of the cell (2)such that the shelf screen (3) is firmly held in place without furtherholding devices. When the shelf screen (3) is used with an agitator (4)of the design shown in FIG. 2 said screen has a hole in its center toaccommodate the shaft of agitator (4). The clearance between the shelfscreen (3) and said agitator shaft is as small as possible withoutaffecting the operation of the agitator (4). It is believed that personsof ordinary skill can easily devise other retaining methods to suspendthe shelf screen (3) in the filtration cell (2) above the rotatingportion (4 a) of the agitator (4). For example, inwardly projecting tabs(not shown) may be affixed to the inner wall of the cell (2), or theymay be integrally formed with the cell wall. Also, a tight fittingO-ring can be installed in a groove (not shown) of the wall of the cell(2) with a portion thereof extending into the cell for supporting thecircumferential edge of a screen shelf thereon.

Moreover, sometimes the sample to be tested has one or more activeingredients carried on, or embedded in, a substrate which does notdisintegrate, or which does not disintegrate completely. Such samplesare said to be “non-disintegrating dosage forms” and are common.Non-disintegrating dosage forms will always produce large solidparticles which would interfere with operation of the agitator (4) ifallowed to sink to the base (36) of the filtration cell (2). Thus,filtration cells having a shelf screen (3) are particularly well-suitedfor conducting dissolution testing of non-disintegrating dosage forms.

Shelf screens (3) useful in the practice of this invention may, forexample, be any of the commercially available mesh screens that arecompatible with preventing large solid particles interfering with theagitator while allowing free passage of release media such that themixing provided by the agitator (4) is still effective in the portion ofthe cell (2) above the shelf screen (3). Thus, suitable screens have amesh size of from 200 mesh to 10 mesh. For example, without limitation,screens having a mesh size of from 50 to 16 mesh have been found to beparticularly useful.

The material of construction of the screens used in the screen shelf canbe of any material compatible with the release medium but must havesufficient rigidity that it does not sag or move during operation. Aparticularly suitable material of construction of the screens isstainless steel, being both compatible with the typical release mediaand of sufficient rigidity. As will be clear to persons having ordinaryskill in the relevant art, less rigid screens can be used when combinedwith a suitable support.

Shelf screens (3) useful in the practice of this invention may, forexample, be any of the commercially available mesh screens that arecompatible with preventing large solid particles interfering with theagitator, while allowing free passage of release media and dissolvedsample, such that the mixing provided by the agitator (4) is stilleffective in the portion of the cell (2) above the shelf screen (3).

The content removal assembly (7) is configured to remove liquid andsmall sized particle solids from the filtration cell (2) for transport,along with liquid from a reservoir (22) to a second filtration cell(10). The reservoir (22) is connected to a pump (9) such that the liquidfrom the reservoir (22) is fed through the content removal assembly (7),to an inlet (29) of the second filtration cell (10). The filtration cell(10) is equipped with a tight fitting lid (25), a pH sensor (13), astirrer (11), two inlets (29 and 30), and an outlet positioned to allowremoval of filtered liquid (32). The second filtration cell (10) may ormay not also have a screen shelf (not shown) which may be configured andoperate similarly to the shelf screen (3) as described above in thefirst filtration cell (2). If the second filtration cell (10) does havea shelf screen, the filtration membrane (12) positioned underneath therotating portion (4 a) of the agitator (4), as shown schematically inFIG. 1 is still required.

Another reservoir (23) is connected to a pump (15) and to one of theinlets (30) of the filtration cell (10), such that liquid from thereservoir (23) is transferred into the filtration cell (10). The outlet(32) is connected to a flow-thru uv cell (16). The outlet of the uv cell(16) is connected to the inlet (31) of a third cell (17). The pH sensor(13) is electrically connected to a pH controller (14). The power supplyto pump (15) is connected to the output relay of the pH controller (14)such that the pump (15) is turned on when the pH as measured by the pHsensor (13) is below a target value, and is turned off when said pH isabove a target value.

The third cell (17) is equipped with a tight fitting lid (26), a stirrer(18), a dip-tube (19), and an outlet (33). The outlet (33) is connectedto the inlet of a flow-thru uv cell (20). The outlet from the uv cell(20) is directed to waste or any suitable reservoir (34). A means fortemperature control may also be provided to manage the temperature ofthe third cell (17) and it contents, but this is not necessary.

In this embodiment, the filtration cell (2) and immediately associatedequipment represents the gastric chamber, or stomach, of a human; thesecond filtration cell (10) and immediately associated equipmentrepresents the intestinal tract of a human; and the third cell (17) andimmediately associated equipment represents the circulatory chamber, orblood, of a human.

Each of the flow-thru uv cells (5, 16, and 20) is placed in a suitableuv spectrophotometer capable of measuring the absorbance of the cellcontents at the desired wavelength.

When control of the temperature is required any or all of the threecells can be placed in a suitable heated enclosure, for example an ovenor a heating bath, which are very well known in the industry.

In one embodiment, reservoir (21) is filled with simulated gastricfluid, reservoir (22) is filled with simulated intestinal fluid, andreservoir (23) is filled with 0.8M aqueous sodium hydroxide solution. Tostart a test, the pumps are operated to fill each of the chambers to thedesired volumes, and then run for sufficient time to establish that theflow rate from each pump is as desired and the pH of cell (10) ismaintained within the target range. The uv cells are checked to makesure that they contain no air bubbles.

In one embodiment the sample addition port (8) of the filtration cell(2) is a hole with a rubber stopper (not shown per se). For saidembodiment the pumps are momentarily stopped, the stopper is removed,and the sample to be tested is added to the filtration cell (2). Thestopper is immediately replaced and the pumps restarted.

In another embodiment, the sample addition port (8) may be an opening(not shown) in the lid (24) of the filtration cell (2), to which adevice is sealingly attached which has a plunger and basket assembly ora plunger and coil assembly (not shown per se, but description in U.S.Patent Application Publication No. US2007/0160497). The basket of such adevice is typically made of mesh and is sized and shaped to hold asample while it is passed through the opening in the lid (24) andcontacted with the liquid media in the cell (2) to dissolve.Non-disintegrating dosage forms often swell in size during contact withthe liquid media and, therefore, delivery of non-disintegrating dosageforms using the aforesaid plunger and basket assembly is not practical.The coil of such a device is typically made of a length of steel wirearranged in a coil shape to hold a sample therein. While a coil mayallow for swelling of the non-disintegrating dosage form, it is stillpossible for large solid particles to form during disintegrating of thesample and fall to the base of the cell where they interfere withoperation of the rotating portion (4 a) of the agitator (4). The shelfscreen (3) of the present invention enables testing ofnon-disintegrating dosage forms in the filtration cell (2) by allowingplacement of the dosage form (sample) on the shelf screen (3) duringdissolution and, thereby, avoiding use of the plunger and basket, orplunger and coil, assembly and avoiding interference with operation ofthe rotating portion (4 a) of the agitator (4) by undissolved orpartially dissolved solids.

Exposure to the fluid in the gastric chamber causes the sample to bepartially or completely disintegrated, and/or dispersed, and/ordissolved. The dissolved portion exits the gastric chamber via thecontent removal assembly (7) together with small particles ofundissolved drug and/or excipient. Dissolved drug and/or dissolvedexcipient leaves the gastric chamber through the outlet (27). The liquidthat exits though outlet (27) passes through the UV uv cell (5), whereits UV absorbance at any desired wavelength is continuously monitored.Said liquid is continuously returned to the gastric chamber via theinlet (28). The material exiting the cell (2) via the content removalassembly (7) mixes with simulated intestinal fluid introduced from thereservoir (22) via the pump (9). This mixture then enters the intestinalchamber (10) via the inlet (29).

In the intestinal chamber (10), the incoming mixture is mixed with thecontents of said chamber together with sodium hydroxide solutionentering from pump (15). Because the sodium hydroxide flow is controlledby the pH of the contents of the cell (10) the result is that the acidpresent in the gastric fluid portion of the incoming mixture isneutralized. In the intestinal chamber (10), the undissolved portion ofthe incoming mixture has further opportunity to dissolve. Dissolved drugand/or dissolved excipient exits the intestinal chamber through theoutlet (32). The filter membrane (12) prevents any undissolved drugand/or undissolved excipient from exiting said chamber. The liquid thatexits though outlet (32) passes through the UV cell (16), where as UVabsorbance at any desired wavelength is continuously monitored. Theliquid exiting the UV cell (16) then enters the circulatory chamber viathe inlet (31).

In the circulatory chamber the incoming medium is mixed with the mediumalready present in said chamber. The resulting mixture continuouslyexits the chamber via the dip-tube (19) and outlet (33). The liquid thatexits though outlet (33) passes through the UV cell (20), where its UVabsorbance at any desired wavelength is continuously monitored.

The data collected from the spectrophotometer can be used to calculatethe instantaneous concentration of the active substance. The data can beused to characterize the release rate and the total amount of activesubstance released. Measuring the concentration of active substance inthe effluent collected in the collection reservoir (34) permits thecalculation of the total amount of active substance released.

While the embodiment of the invention described above and illustrated bythe examples uses constant composition of release fluids within eachtest, it is clear that the compositions can be changed with time, forexample, as taught by Waaler (J Pharm Sci, 82, 764-766, 1993), tosimulate changing conditions within the body.

Test method variables are composition of release media, residence timein each of the three chambers, amount of the sample being tested, andtemperature. By adjusting these variables it is possible to obtain arelease rate profile that matches the plasma concentration profileobserved in vivo. When practiced in the pharmaceutical industry thepreferred temperature is 37° C., and the preferred composition of therelease media are simulated gastric and simulated intestinal fluids,recommended compositions for both of which can be found in the mostrecent edition of the US Pharmacopeia. It is also clear to one skilledin the art that other additives, such as enzymes, bile acids, andsurfactants, can be included where their need is demonstrated. The USFDArecommends that dissolution conditions be physiologically relevant.However, it is clear to one skilled in the art that the presentinvention can be adapted for conditions that are not physiologicallyrelevant. Such conditions may be desirable when considerations such asspeed of operation, unusual solubility, or non conventional dosage formsare taken into account. For example, applicant has determined in somecases that by proportionally reducing residence times, the time scale ofthe test can be considerably shortened without loss of usefulinformation.

The invention can be used to test many different types of formulation.These can include, but are not restricted to, tablets, powders, pills,syrups, fast-melt tablets, hard capsules and soft capsules. The mediumanalysis device includes, but is not limited to, any detector known inthe art that generates physical and/or chemical data of a pharmaceuticalor active test agent, e.g., the use of a UV spectrophotometer as themethod of analysis. In a preferred embodiment, the detector is capableof acquiring data characteristic of a particular agent by methodselected from the group consisting of ultraviolet radiation, infraredradiation, nuclear magnetic resonance, Ramen spectroscopy,electrochemical, biosensors, refractometry, optical activity, andcombinations thereof. Any in-line detector known in the art that isapplicable to the active substance and release medium can be also beused. Preferably, the medium dissolution analysis device is a detectorthat has a sensor communicatively attached thereto. In the preferredembodiment, there is at least one medium dissolution analysis device perdissolution chamber. For example, for each sample to be analyzed thereis a corresponding medium dissolution analysis device capable ofcontinuously generating physical and/or chemical data characteristic ofthe agent to be analyzed.

The medium analysis device preferably includes a detector operativelyassociated with the dissolution medium for at least the time periodrequired for the dosage form to release the maximum releasable quantityof therapeutically active agent and a data processor for continuallyprocessing the generated data for at least the time period required forthe dosage form to release the maximum releasable quantity oftherapeutically active agent to obtain a dissolution profile of thedosage form. The data processor may be any device capable ofcontinuously processing the data generated by the detector. In apreferred embodiment, the data processor is a computer. The datagenerated by the detector is preferably stored and/or analyzed by thecomputer. In a particularly preferred embodiment, the data collector isa computer that has data processing software. The data is preferablycontinuously processed by the software as it is received from thedetector. In the preferred embodiment of the present invention, thedetector measures the concentration of the therapeutically active agentin the media surrounding the dosage form such as in simulated gastric orintestinal fluid. By measuring the concentration of the agent in thesurrounding media, the amount of agent released from the dosage form canbe calculated.

The invention can also be used by removing samples from the chambersdirectly or from the effluent discharge of the chambers instead of, orin addition to in-line analysis. In such an embodiment the analyticalmethods can be any method known in the art, including but not limitedto, Gas chromatography, liquid chromatography, high performance liquidchromatography (HPLC), colorimetry, uv spectroscopy, IR spectroscopy,Raman spectroscopy, near IR spectroscopy, bio-sensors, electrochemicalmethods, mass spectroscopy, and nuclear magnetic spectroscopy.

In the most preferred embodiment the medium analysis is performedin-line using uv spectroscopy.

It is clear to one skilled in the art that any combination of the mediumanalysis devices can be used as appropriate for the data required.

In another embodiment the absorption of active substance in the stomachcan be simulated by not returning to the gastric chamber, all or part ofthe medium exiting the gastric chamber via the second outlet. The flowrate of said medium can be adjusted so that the removal rate correspondsto the in vivo gastric absorption.

The filtration cells (2 and 10) can be of any design that provides therequirements of agitation, desired volume, filtration speed, filtrationefficiency, and compatibility with the active substance and the releasemedia. The preferred filtration cells are continuous, stirred,filtration cells, such as the AMICON™ stirred ultrafiltration cellmodels 8003, 8010, 8050, 8200, and 8400, commercially available fromMillipore Corporation. The lids and height of these cells can bemodified to fulfill the requirements as described hereinabove.

The third cell (17) can be of any design that provides the requirementsof agitation, desired volume, and compatibility with the activesubstance and the release media.

The pumps useful in the practice of the present invention can be anypump capable of attaining the desired flow rate and maintaining saidflow rate constant throughout the test. These include but are notlimited to, general purpose positive displacement pumps, peristalticpumps, diaphragm pumps, HPLC quality positive displacement pumps, andcentrifugal pumps. Preferred pumps useful in the invention areperistaltic pumps, diaphragm pumps, and HPLC quality positivedisplacement pumps. Most preferred are peristaltic pumps and HPLCquality positive displacement pumps.

Heating devices useful in the practice of the present invention can beany of those known in the art that give sufficiently uniform andaccurate temperature control. The preferred heating device will be ableto control the temperature to within +/−2° C. of the desiredtemperature. The more preferred heating device will be able to controlthe temperature to within +/−1° C. of the desired temperature. The mostpreferred heating device will be able to control the temperature inconformity with the most current recommendations in the US Pharmacopeiaand like sources.

Tubing used for the content removal assembly (7) can be any tubingcompatible with the release medium and the test sample. The length ofsaid tubing is adjusted such that the lower end is below the surface ofthe liquid in the filtration cell (2). The cross-sectional diameter ofthe tubing is selected so that small particles are carried up the tubingby the flow of the release medium and so that particles do not clog thetubing. In practice, the inventors have determined that tubing with aninternal diameter of 0.5 to 3.0 mm fulfills these requirements for flowrates to the cell (2) in the range 0.5 to 2.5 ml/min. For other flowrates other internal diameters may be needed. It is clear to one skilledin the art that suitable internal diameters for the said tube can beselected by trial and error, or by calculation using suitablehydrodynamic considerations.

The medium analysis sensor and controller used with the intestinalchamber can be any combination of sensor and controller that measuresand permits control of physical characteristics such as, but not limitedto, pH, osmolarity, conductivity, and concentration of specific ions.

The preferred medium analysis sensor and controller are any pH sensorand pH controller available in the art that permit the control of the pHin the intestinal chamber to within the target range. The most preferredmedium analysis sensor and controller are any pH sensor and pHcontroller available in the art that has an accuracy of +/−0.02 pHunits.

In the preferred embodiment the pH in the second cell (10) is controlledto the same value as that of the simulated intestinal fluid. It is clearto one skilled in the art that the pH in the said cell can be any valueachievable by addition of either an acid or a base through the deliverysystem defined by the reservoir (23), the pump (15), and the inlet (30),and is not limited to the pH of the fluid in the reservoir (22).

The solution used to adjust the pH of the second cell can be acidic orbasic. The preferred concentration of acid or base in said solution isone that requires a flow rate of said solution to be not more than 10%of the total flow of the other release media. The most preferredconcentration of acid or base in said solution is one that requires aflow rate of said solution to be not more than 2% of the total flow ofthe other release media.

The number of cells used in the equipment can be varied depending on theinformation required. Three cells, as described in one embodiment above,is the preferred number when correlation with blood plasma concentrationdata is required. When drug absorption rate data is required it is onlynecessary to operate the combination of gastric and intestinal chambers.A further possibility is to add a buccal dissolution cell before thegastric chamber such that the effluent from the buccal dissolutionchamber enters an inlet in the gastric chamber. Said addition can beused for either drug absorption or blood plasma concentration data.

The volumes of the three chambers and the flow rates of the variousmedia are calculated based on the desired residence times for each ofthe chambers. This calculation is well known in the art and is describedhereinabove.

Residence times in each of the chambers useful in the practice of thisinvention can be any value required to give Level A IVIVC. The preferredresidence times are those that have physiological relevance. Theapplicant has determined by experimentation that the following ranges ofresidence times are useful: gastric chamber, 5-60 minutes; intestinalchamber, 1-90 minutes; circulatory chamber, greater than 30 minutes.

It is known to those skilled in the art that the safe and effective useof flow controlling devices such as pressure feed systems and pumpsrequires the inclusion of various other mechanical, electrical andelectronic equipment. Said equipment includes, but is not limited to,pressure relief valves, check valves, pressure relief piping, pressurecontrol systems, surge suppressors, surge tanks, de-aerators, electronicflow control systems, proportional control systems, pressure gauges, andflow gauges.

Said correlation in data is achieved by manipulation of test methodvariables including the number of said chambers, number of media, volumeof release medium in each of said chambers, flow rate of release mediumto each of said chambers, amount of the sample being tested, pH of themedia, composition of the media, and temperature.

EXAMPLES Comparative Example 1 Plunger and Basket Assembly, No ShelfScreen

The dissolution equipment was set up with the following conditions usinga 20 mesh basket, as described in US20070160497(A1). Simulated GastricFluid (SGF) and Simulated Intestinal Fluid (SIF, pH 6.8) were preparedaccording to the US Pharmacopoeia 30.

SGF flow to Cell 1 2.50 ml/min SIF flow to Cell 2 7.35 ml/min pH of Cell2 6.8 Cell 1 volume 50 ml Cell 2 volume 150 ml Cell 3 volume 1600 mlTemperature 37° C.

One half of a 200 mg ADVIL™ Advil tablet was placed in the basket. (Awhole Advil tablet was too large to fit in the basket.) Theplunger/basket was placed in its raised position. When conditions oftemperature, and flow rates were steady and at targeted values thebasket was introduced into the fluid in the first cell by pushing theplunger to its lowered. position. The tablet disintegrated in thebasket, but the disintegrated solids did not leave the basket andtherefore no solids transfer occurred. Based on observation, it appearedthat the particle size of the disintegrated solid was too large to passthrough the screen which formed the basket. Efficient solids transfer isan essential part of the test procedure, so this apparatus and methodwas unacceptable.

Comparative Example 2 Plunger and Coil Assembly, No Shelf Screen

Example 1 was repeated except that the basket was replaced with a coilof steel wire arranged to hold a whole 200 mg Advil tablet, and the testrepeated as described. When the tablet was introduced into the fluid inthe first cell the tablet disintegrated but the disintegrated solidsinterfered with the stirrer blade and stopped it. Efficient mixing is anessential part of the test procedure, so this apparatus and method wereunacceptable.

Example 1 Plunger and Coil Assembly, Screen Shelf Positioned AboveStirrer Blade

Example 2 was repeated except that a shelf screen (20 mesh) was used inthe chamber of the dissolution cell. When the tablet was introduced intothe fluid it disintegrated and the disintegrated solids transferredcompletely to the second cell. The stirrer continued operating. Thisexample demonstrates that the shelf screen solves the problem of solidstransfer and mixing for disintegrating dosage forms.

Example 2 Sample Addition Port Covered by a Simple Cap, Screen ShelfPositioned Above Stirrer Blade

In this example a shelf screen was included in the chamber of Cell 1 ofa system having two cells (Cell 1 and Cell 2). Cell 1 also included aslider valve assembly which facilitated introduction of samples duringcontinuous operation of the system.

Water was used as a surrogate for both SGF and SIF. No pH control wasused. The test was set with the following conditions.

Water flow to Cell 1  3.0 ml/min Water flow to Cell 2  6.0 ml/min Cell 1volume  70 ml Cell 2 volume 190 ml Cell 3 volume 500 ml TemperatureAmbient

With the slider valve in closed position, approx ¼ of a tablet ofbrilliant blue dye (Presto Dye, “Trace-a-Leak”) was placed in the slidervalve and the cap screwed into place. Brilliant blue dye was selectedfor this example to permit observation of disintegration anddissolution. When the flow rates were steady and at targeted values theslider valve was opened fully. The tablet dropped into the fluid andcame to rest on the screen shelf where it disintegrated. Dissolved dye,undissolved dye, and insoluble excipients transferred completely to thesecond cell. The stirrer continued to operate without interruption. Thisexample demonstrates that the slider valve/screen shelf combinationpermits addition of a disintegrating tablet into Cell 1 without the useof a basket and without requiring the flows to be stopped or requiringthe cell to be opened.

We claim:
 1. An apparatus for conducting dissolution tests comprising: a) a first chamber comprising a base and a shelf screen and being capable of transferring solid particles to a second chamber; wherein said shelf screen is a mesh screen compatible with said medium and having a have a mesh size of from 200 mesh to 10 mesh; wherein said first chamber additionally comprises tubing configured to remove liquid and particle solids from below said shelf screen to said second chamber; wherein said first chamber additionally comprises a lid, and said first chamber additionally comprises a hole in the lid for sample addition; b) said second chamber connected in series to said first chamber via said tubing and being capable of retaining solids; c) at least one supply of media that can be continuously passed into one or more of said chambers; d) a medium analysis device that analyzes effluent from said chambers for substances of interest in the tests; e) a heating device that controls temperature of medium in each of said chambers; wherein each of said chambers has a sample addition port and an agitator that mixes the sample and medium; and wherein said agitator of said first chamber is proximate to said base and said shelf screen is positioned in said first chamber, above said agitator, on an opposite side of said agitator from said base.
 2. The apparatus according to claim 1, wherein said dosage form is a non-disintegrating dosage form wherein at least a portion of said substrate does not dissolve in said medium.
 3. The apparatus according to claim 1, wherein said shelf screen has a mesh size of from 50 to 16 mesh.
 4. The apparatus according to claim 1, further comprising: a third chamber connected in series to said second chamber.
 5. The apparatus according to claim 4, further comprising: at least one supply of media that can be continuously passed into said third chamber; stirrer in said third chamber; medium analysis device that analyzes effluent from said third chamber for substances of interest.
 6. The apparatus according to claim 1, wherein said heating device controls temperature to within +/−2° C. of a desired temperature.
 7. The apparatus according to claim 6, wherein said desired temperature is 37° C. 